DE3601248A1 - SUBSTITUTED 4-AMINO-3-HYDROXYBUTTERIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THESE AGENTS AND THEIR USE - Google Patents

Description

From EP-A-1 52 255 and EP-A-1 55 809 tripeptide Derivatives and their use known as renin inhibitors.

New substituted 4-amino-4-hydroxybutyric acid Derivatives found to be highly effective in vitro and in vivo inhibit the enzyme renin.

The invention relates to compounds of the formula I. in which

• R ⁴ a ₁ ) denotes a radical of the formula II or III, wherein
  • R ^{5 is} hydrogen or (C ₁ -C ₇ ) alkyl and
    R ^{6 is} hydrogen, (C ₁ -C ₇ ) -alkyl or by hydroxy, (C ₁ -C ₅ ) -alkoxy, (C ₁ -C ₅ ) -alkylthio, carboxy, (C ₁ -C ₅ ) -alkoxycarbonyl, Cl, Br, (C ₁ -C ₅ ) alkylamino, di- (C ₁ -C ₅ ) alkylamino, (C ₁ -C ₅ ) alkoxycarbonylamino or (C ₁ -C ₁₅ ) aralkyloxycarbonylamino monosubstituted (C ₁ - C ₇ ) alkyl,
    m = 0, 1, 2, 3 or 4,
    n = 1, 2, 3, 4, 5 or 6,
    the double bond in the rest of the formula III in the case n = 0 preferably has the E configuration, otherwise preferably the Z configuration and
    Ar for (C ₆ -C ₁₄ ) aryl, which may be replaced by one or two identical or different radicals from the series F, Cl, Br, J, hydroxy, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxycarbonyl, amino, (C ₁ -C ₇ ) alkylamino, di (C ₁ -C ₇ ) alkylamino, carboxy, carboxymethyloxy, amino (C ₁ -C ₇ ) -alkyl, (C ₁ -C ₇ ) -alkylamino- (C ₁ -C ₇ ) -alkyl, di- (C ₁ -C ₇ ) -alkylamino- (C ₁ -C ₇ ) -alkyl, (C ₁ -C ₇ ) alkoxycarbonylmethoxy, carbamoyl, sulfamoyl, (C ₁ -C ₇ ) alkoxysulfonyl, sulfo and guanidinomethyl, or for the remainder of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaromatic with at least 1 C atom, 1-3 N atoms and / or 1 S or O atom as ring members, where Ar can also be bonded via -O-,
• a ₂ ) a residue of an amino acid from the series phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, β-2-thienylalanine, β-3-thienylalanine, 4-chlorophenylalanine, 4-chlorophenylalanine, methionine sulfone linked via a peptide bond Methionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine, O-methyltyrosine, O-benzyltyrosine, O-tert.-butyltyrosine, phenylglycine, 1-naphthylalanine, 2-naphthylalananoline 4-naphthylalanine , 3-fluorophenylalanine, 4-fluorophenylalanine, norleucine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, homophenylalanine, DOPA, O-dimethyldopa, 2-amino-4- (2-thienyl) butyric acid, 2-amino -4- (3-thienyl) butyric acid, 3- (2-thienyl) serine, (Z) -dehydrophenylalanine and (E) -dehydrophenylalanine, whose C-terminal carboxyl group is free, reduced to CH ₂ OH or
  as an amide which has a C-terminus of the formula -NR ⁷ R ⁸ , in which R ⁷ and R ^{8 are} identical or different and are for
  • Hydrogen,
    (C ₁ -C ₁₀ ) alkyl optionally substituted by amino, (C ₁ -C ₅ ) alkoxycarbonylamino, (C ₇ -C ₁₅ ) aralkylcarbonylamino, heteroarylamino, in which the remainder of the heteroaromatic is as defined above under (a ₁ ) is hydroxy, (C ₁ -C ₅ ) alkoxy, sulfo, carboxy or (C ₁ -C ₅ ) alkoxycarbonyl is monosubstituted,
    (C ₆ -C ₁₄ ) aryl (C ₁ -C ₄ ) alkyl, optionally in the aryl part by amino, carboxy, (C ₁ -C ₅ ) alkoxycarbonyl, amino (C ₁ -C ₅ ) alkyl , (C ₁ -C ₅ ) alkoxycarbonylamino (C ₁ -C ₅ ) alkyl, (C ₇ -C ₁₅ ) aralkoxycarbonylamino- (C ₁ -C ₅ ) alkyl, (C ₁ -C ₅ ) alkoxycarbonyl- (C ₁ -C ₅ ) alkoxy, carboxy- (C ₁ -C ₅ ) alkoxy or guanido (C ₁ -C ₅ ) alkoxy is monosubstituted, or
    Heteroaryl- (C ₁ -C ₄ ) -alkyl, the remainder of the heteroaromatic as Ar being defined under (a ₁ ), or
    represents a radical of the formula IV, wherein p = 1, 2, 3 or 4, q = 4 or 5 and Q is N or CH or p = 0, q = 4 or 5 and Q is CH and wherein a CH ₂ group in the ring by NH , O, S, CO, N-Bzl, NZ or N-BOC can be replaced, or
• a ₃ ) means a residue of a dipeptide from the series Leu-Asn, Ile-His, Ile-Arg and Ile-Lys linked via a peptide bond, its C-terminus as a free COOH group, which optionally reduces to the CH ₂ OH group is present as CONH ₂ or as COOR ⁹ with R ⁹ = (C ₁ -C ₇ ) alkyl and in which the ε-amino function of the lys is optionally by (C ₁ -C ₅ ) alkoxycarbonyl or (C ₇ -C ₁₅ ) -Aralkyloxycarbonyl is protected;
• R ¹ b ₁ ) is absent or is hydrogen,
• b ₂ ) (C ₁ -C ₂₀ ) alkyl, which may be replaced by one, two or three identical or different radicals from the series hydroxy, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkanoyloxy, Carboxy, (C ₁ -C ₇ ) alkoxycarbonyl, (C ₁ -C ₈ ) alkanoyloxy, Cl, Br, amino, (C ₁ -C ₇ ) alkylamino, di- (C ₁ -C ₇ ) alkylamino, (C ₁ -C ₅ ) alkoxycarbonylamino or (C ₇ -C ₁₁ ) aralkyloxycarbonylamino is substituted,
  (C ₃ -C ₈ ) cycloalkyl,
  (C ₃ -C ₈ ) cycloalkyl- (C ₁ -C ₁₀ ) alkyl or
  (C ₆ -C ₁₄ ) -Aryl- (C ₁ -C ₈ ) -alkyl, which may be in the aryl part by one or two identical or different radicals from the series, F, Cl, Br, hydroxy, (C ₁ -C ₇ ) Alkoxy, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxycarbonyl, amino or trifluoromethyl is substituted, or
• b ₃ ) is a radical of the formula V, Ra-W-, 6 (V)
  • wherein W is -CO-, -O-CO-, -SO ₂ - or -NH-CO- and Ra is hydrogen, (C ₁ -C ₁₀ ) alkyl, which is optionally mono- or di-unsaturated, and optionally by up to 3 identical or different radicals from the series hydroxy, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkanoyloxy, carboxy, (C ₁ -C ₇ ) alkoxycarbonyl, Cl, Br, amino, (C ₁ -C ₇ ) alkylamino, di- (C ₁ -C ₇ ) alkylamino, (C ₁ -C ₅ ) alkoxycarbonylamino, (C ₇ -C ₁₅ ) aralkoxycarbonylamino or 9-fluorenylmethyloxycarbonylamino is monosubstituted,
    (C ₃ -C ₈ ) cycloalkyl,
    (C ₃ -C ₈ ) cycloalkyl- (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₄ ) aryl, which may be replaced by one or two identical or different radicals from the series F, Cl, Br, J, Hydroxy, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxycarbonyl, amino, optionally substituted with up to 2 halogen-substituted anilino and trifluoromethyl,
    (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₆ ) alkyl, in which the aryl part is optionally as defined above for aryl,
    Heteroaryl or heteroaryl- (C ₁ -C ₆ ) -alkyl, where the rest of the heteroaromatic is in each case defined as Ar under (A ₁ ), or
• b ₄ ) a radical from the series (2S) -trans-4-hydroxy-1-acyl-pyrrolidinyl-2-carbonyl, 5-pyrrolidone-2S-carbonyl, α-methoxycarbonyl-α-acylacetyl, 1-acyl- (2R , 3aR, 6aR) -octahydro-cyclopenta [b] pyrrole-2-carbonyl and 1-acyl- (2S, 3aS, 6aS) -octahydro-cyclopenta [b] pyrrole-2-carbonyl, with acyl meaning (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₅ ) alkoxycarbonyl or (C ₇ -C ₁₅ ) alkoxycarbonyl or (C ₇ -C ₁₅ ) aralkyloxycarbonyl,
• A c ₁ ) denotes a radical of the formulas VI or VII,
  • in which
    r = 1, 2 or 3,
    s = 1, 2 or 3 and
    R is (C ₁ -C ₇ ) alkyl, or
• c ₂ ) denotes a residue of an amino acid linked to R ¹ and C-terminal to B of an amino acid which is defined as under (a ₂ ),
• B d ₁ ) if R ^{4 is} as defined under (a ₁ ), means an N-terminal with A and C-terminal with the NH group of formula I linked residue of an amino acid which is as defined under (a ₂ ), or
• d ₂ ) if R ^{4 is} as defined under (a ₂ ) or (a ₃ ), an N-terminally linked A and C-terminally linked to the NH group of formula I of an amino acid from the series 2-thienylalanine, 3 -Thienylalanine, cyclohexylglycine, phenylglycine, aspartic acid, asparagine, glutamic acid, glutamine and methionine sulfone,
• R ^{2 is} hydrogen, (C ₁ -C ₁₀ ) alkyl, (C ₄ -C ₇ ) cycloalkyl, (C ₄ -C ₇ ) cycloalkyl- (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₄ ) Aryl or (C ₆ -C ₁₄ ) aryl (C ₁ -C ₄ ) alkyl and
• R ^{3 is} hydrogen, (C ₁ -C ₁₀ ) alkyl, (C ₆ -C ₁₄ ) aryl or (C ₆ -C ₁₄ ) aryl (C ₁ -C ₄ ) alkyl,

and their physiologically tolerable salts.

The C atoms substituted by R ² , hydroxy and R ³ can each have the R, S or R, S configuration.

Alkyl can be straight-chain or branched. Corresponding applies to residues derived therefrom, such as. B. alkoxy, alkylthio, Alkylamino, dialkylamino, alkanoyl and aralkyl.

Cycloalkyl also includes alkyl-substituted radicals, such as e.g. B. 4-methylcyclohexyl or 2,3-dimethylcyclopentyl understood.

(C ₆ -C ₁₄ ) aryl is, for example, phenyl, naphthyl, biphenylyl or fluorenyl; phenyl is preferred. The same applies to residues derived therefrom, such as. B. aryloxy, aroyl, aralkyl and aralkyloxy. Preferred aralkyl radicals are benzyl and phenethyl.

Among a residue of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaromatics at least 1 C atom, 1-3 N atoms and / or 1 S or O Atomic ring members are understood to be residues of heteroaromatics, like for example in Katritzky, Lagowski, Chemistry of heterocycles, Berlin, Heidelberg 1968, page 3-5 are defined. Monocyclic heteroaromatics are e.g. B. thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, Pyrazine, pyrimidine, pyridazine, 1,2,4-triazole, thiazole, Isothiazole, oxazole and isoxazole. Bicyclic heteroaromatics are z. B. benzothiophene, benzofuran, indole, isoindole, indazole, Benzimidazole, quinoline, isoquinoline, phthalazine, Quinoxaline, quinazoline and cinnoline. The same applies for residues derived from heteroaryl, such as. B. heteroaryloxy, Heteroaryl and heteroaryl alkyl.  

The amino acids A and B in formula I are linked to one another by an amide bond; they are natural or unnatural α-amino acids of the L, D or D, L configuration, preferably the L configuration. The same applies to amino acids or their derivatives as radicals R ⁴ .

Salts of compounds of formula I are in particular pharmaceutically acceptable or non-toxic salts to understand.

Such salts are used, for example, by compounds of Formula I, which acidic groups, e.g. B. carboxy, contain formed with alkali or alkaline earth metals, such as Na, K, Mg and Ca, as well as with physiologically compatible organic Amines such as B. triethylamine and tri- (2-hydroxy) - ethyl) amine.

Compounds of formula I which basic groups, e.g. B. an amino group or a guanidino group, form salts with inorganic acids, such as. B. hydrochloric acid, Sulfuric acid or phosphoric acid and with organic carbon or sulfonic acid, such as. B. acetic acid, citric acid, Benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid.

Preference is given to compounds of the formula I in which R ^{4 is} as defined under (a ₁ ) above. Compounds in which

• R ^{5 is} hydrogen or methyl and / or
• R ⁶ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, (C ₁ -C ₅₎ alkoxycarbonylmethyl, (C ₁ -C ₅₎ mean -Alkoxycarbonylethyl or methylthioethyl and / or wherein
• Ar for phenoxy, phenyl, 2-, 3- or 4-pyridyl, 4-imidazolyl, 1-, 3- or 4-isoquinolyl, 2-, 3- or 4-carboxyphenyl, 2-, 3- or 4- (C ₁ -C ₇ ) alkoxycarbonylphenyl, preferably 4-methoxycarbonylphenyl or 3-tert-butoxycarbonylphenyl, 2-, 3- or 4-aminophenyl, mono- or di- (C ₁ -C ₇ ) alkylaminophenyl, preferably 3-methylaminophenyl or 3-dimethylaminophenyl, 2-, 3- or 4-carbamoylphenyl, 3-sulfamoylphenyl, 3-sulfophenyl, amino (C ₁ -C ₇ ) alkylphenyl, preferably 2-, 3- or 4-aminomethylphenyl, 3- (methylamino- methyl) phenyl, 3- (N, N-dimethylaminomethyl) phenyl, (C ₁ -C ₇ ) alkoxycarbonylmethoxyphenyl, preferably 2-, 3- or 4-methoxycarbonylmethoxyphenyl or 3-tert-butoxycarbonylmethoxyphenyl, 2-, 3- or 4-carboxymethyloxyphenyl, (C ₁ -C ₇ ) alkoxyphenyl, preferably 2-, 3- or 4-methoxyphenyl, or 2-, 3- or 4-guanidinomethylphenyl.

Of the compounds of the formula I in which R ^{4 is} as defined under (a ₂ ) above, preference is given to those in which R ^{4 represents} the residue of an amino acid amide with the C-terminus -NR ₇ R ⁸ , in which R ⁷ and R ^{8 are the} same or different and are methyl, 10-aminodecyl, 9-aminononyl, 8-aminooctyl, 7-aminoheptyl, 6-aminohexyl, 5-aminopentyl, 4-aminobutyl or the N-BOC or NZ-protected derivatives of the mentioned ω Aminoalkyl residues, (2-pyrimidinylamino) ethyl, 2-sulfoethyl, 8-carboxoctyl, 7-carboxyheptyl, 6-carboxylhexyl, 7-methoxycarbonyl-heptyl, 2-pyridylaminoethyl, phenethyl or benzyl, both of which are optionally in the phenyl part in 2 -, 3- or 4-position by amino, in 2-, 3- or 4-position by aminomethyl, in 3-position by BOC-aminomethyl or guanidinomethyl, in 2-, 3- or 4-position by carboxy, in 3 Position are substituted by tert-butoxycarbonyl, in the 2-, 3- or 4-position by carboxymethoxy or in the 3-position by tert-butoxycarbonylmethoxy, 2-, 3- or 4-pyridylmethy 1,4-imidazolylethyl, 3-indolylethyl, 4-piperidyl, 4-piperidyl- (C ₁ -C ₄ ) -alkyl, 2-oxo-1-pyrroldinyl, 2-oxo-1-pyrrolidinyl- (C ₁ -C ₄ ) alkyl, preferably 4- (N-benzyl) piperidyl, 3-morpholinopropyl or 3- (2-oxo-1-pyrrolidinyl) propyl or NR ⁷ R ^{8 represents} morpholino.

Compounds of the formula I with a radical R ⁴ defined above under (a ₃ ) are preferably those in which R ^{4 is} Leu-Asn-NH ₂ , Ile-His-OH, Ile-His-NH ₂ , Ile-Arg-NH ₂ , Ile-Arg-OH, Ile-Arg-OCH ₃ , Ile-Arginol, Ile-Lys (Boc) -OCH ₃ , Ile-Lys-OCH ₃ , Ile-Lys-OH or Ile-Lys-NH ₂ .

R ¹ is preferably absent, means hydrogen or represents (C ₁ -C ₁₀ ) alkyl, cyclopentyl, cyclohexyl, cyclopentyl- (C ₁ -C ₁₀ ) alkyl, cyclohexyl- (C ₁ -C ₁₀ ) alkyl, if appropriate substituted phenyl- (C ₁ -C ₈ ) alkyl, H ₂ N- (C ₁ -C ₁₀ ) alkyl, HO- (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₄ ) alkoxy- ( C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonyl- (C ₁ -C ₁₀ ) alkyl, carboxy- (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₈ ) alkanoyloxy - (C ₁ -C ₁₀ ) alkyl, (C ₁ -C ₁₁ ) alkanoyl, such as n-decanoyl, formyl, acetyl, pivaloyl, isovaleryl or isobutyryl, optionally protected amino (C ₁ -C ₁₁ ) alkanoyl, such as 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 4-N-tert-butoxycarbonylaminobutyryl, 5-N-tert-butoxycarbonylaminopentanoyl or 6-N-tert-butoxycarbonylaminohexanoyl, di- (C ₁ -C ₇ ) - alkylamino (C ₁ -C ₁₁ ) alkanoyl, such as dimethylaminoacetyl, (C ₄ -C ₉ ) cycloalkanoyl, such as cyclopropanoyl, cyclobutanoyl, cyclopentanoyl or cyclohexanoyl, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₁₁ ) alkanoyl, such as phenylacetyl, Ph enylpropanoyl or phenylbutanoyl, 2- (o, o-dichloroanilino) phenylacetyl, 2- (N-benzyl-o, o-dichloroanilino) phenylacetyl, optionally by halogen, (C ₁ -C ₇ ) alkyl, (C ₁ - C ₇ ) alkoxy or (C ₁ -C ₇ ) alkoxycarbonyl substituted benzoyl, such as 4-chlorobenzoyl, 4-methylbenzoyl, 2-methoxycarbonylbenzoyl or 4-methoxybenzoyl, pyrrolyl-2-carbonyl, pyridyl-3-carbonyl, benzylsulfonyl, ( C ₁ -C ₁₀ ) alkoxycarbonyl, such as methoxycarbonyl or tert-butoxycarbonyl, halogen-substituted (C ₁ -C ₁₀ ) alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl or 1,1-dimethyl-2,2,2 trichloroethoxycarbonyl, (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₆ ) alkoxycarbonyl, such as benzyloxycarbonyl or 9-fluorenylmethylcarbonyl, (2S) -trans-4-hydroxy-1-acetylpyrrolidinyl-2-carbonyl, α- Methoxycarbonyl-α-benzyloxycarbonylaminoacetyl, N-acetyl- (2S, 3aS, 6aS) -octahydrocyclopenta [b] pyrrole-2-carbonyl or N-acetyl- (2R, 3aR, 6aR) -octahydrocyclopenta [b] pyrrole-2-carbonyl.

Preferred amino acids which are suitable for the radicals A, B and R ⁴ are phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, β-2-thienylalanine, β-3-thienylalanine, 4- Chlorophenylalanine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine, O-methyltyrosine, O-benzyltyrosine, O-tert.-butyltyrosine, phenylglycine, 1-naphthylalanineyl , Norleucine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, homophenylalanine, 2-amino-4- (2-thienyl) butyric acid, (Z) -dehydrophenylalanine or (E) -dehydrophenylalanine. In addition, A is preferably (2S) -benzyloxy-3-phenyl-propanoyl or (2R, S) -2-benzyl-4-oxo-6,6-dimethyl-heptanoyl.

R ² is preferably cyclohexylmethyl, benzyl or isobutyl, R ^{3 is} preferably hydrogen, ethyl, sec-butyl, isobutyl, benzyl, phenethyl or 3-phenylpropyl.

Without being limited to this, they are the following compounds according to the invention are highlighted:

BOC-Phe-His-ACHPA- (1S) -1-methyl-3-phenylpropylamide
BOC-Phe-β-thienylalanine-ACHPA- (1S) -1-methyl-3-phenylpropylamide
BOC-Phe-β-2-thienylalanine-ACHPA- (1S) -1-methyl-3- (2-pyridyl) propylamide
BOC-Phe-β-2-thienylalanine-Sta-Ile-2-pyridylmethylamide
BOC-Phe-β-2-thienylalanine-ACHPA- (1S) -1-methyl-3- (3-aminomethyl) phenyl-propylamide
BOC-Phe-β-2-thienylalanine-ACHPA- (1S) -1-methyl-3- (3-carboxymethoxy) phenylpropylamide
BOC-Phe-β-2-thienylalanine-ACHPA- (1S) -1-methyl-4- (3-carboxymethoxy) phenylbutylamide
BOC-Phe-β-2-thienylalanine ACHPA - [(3S, 4S) -4-methyl-hexan-3-yl] -amide
BOC-Phe-β-2-thienylalanine-Sta-Ile- (3-aminomethyl) benzylamide
Z-Phe-β-2-thienylalanine-Sta-Ile- (3-carboxymethoxy) benzylamide
Fmoc-Phe-β-2-thienylalanine-Sta-Ile- (3-aminomethyl) benzylamide
BOC-β-2-thienylalanine-His-Sta-Ile-2-pyridylmethylamide
Z-Phe-β-2-thienylalanine-Sta-Ile-B-aminooctylamide
Z-Phe-β-2-thienylalanine-Sta-Ile- (3-aminomethyl) benzylamide
Z-Phe-β-2-thienylalanine-ACHPA-Ile- (3-aminomethyl) benzylamide
Z-Phe-His-ACHPA- (1S) -1-methyl-3- (2-pyridyl) propylamide
Z-Phe-His-ACHPA- (1S) -1-methyl-3- (3-aminomethyl) phenylpropylamide
BOC-Phe-His-Sta-Leu-Asn-NH ₂
BOC-Phe-β-2-thienylalanine-Sta-Ile-Arg-OH
BOC-Phe-β-2-thienylalanine-Sta-Ile-Arg-OMe
BOC-Phe-β-2-thienylalanine-Sta-Ile-arginol
BOC-Phe-β-2-thienylalanine-Sta-Ile-Arg-NH ₂

The invention further relates to a method of manufacture of compounds of formula I, characterized in that is that you have a fragment with a terminal Carboxyl group or its reactive derivative with a couples the corresponding fragment with a free amino group, if necessary to protect further functional groups (a) temporarily introduced protective group (s) split off and  the compound thus obtained, if necessary, physiologically in it tolerated salt transferred.

Fragments of a compound of formula I with a terminal Carboxyl group have the following formulas VIIIa-VIIId:

R ¹ -OH (VIIIa)
R ¹ -A-OH (VIIIb)
R ¹ -AB-OH (VIIIc)

Fragments of a compound of formula I with a terminal amino group have the following formulas IXa-IXd: H ₂ NR ⁴ (IXd)

Methods suitable for making an amide bond are z. B. in Houben-Weyl, methods of organic Chemistry, Volume 15/2 described, preferably following methods: Active ester method with N-Hydroxy-succinmid as an ester component, coupling with Propanephosphonic anhydride and the mixed anhydride Pivaloyl chloride method.

The preparation of the used as a starting compound optically active amines of the formulas X and XI

R ⁵ -HN-CH- [CH ₂ ] _n -Ar (X)
R ⁵ -HN-CH-CH = CH- [CH ₂ ] _m -Ar (XI)

wherein m, n , R ⁵ , R ⁶ and Ar are as defined above, is based on optically active α-amino acids, while maintaining their asymmetry center. For this purpose, an N-protected amino acid aldehyde is produced in a known manner, which by an Wittig reaction with a corresponding phosphonium salt gives an olefin of the formula XI. Amines of formula X are obtained therefrom by catalytic hydrogenation. The optical purity of the amines produced can be checked in a known manner by converting them to Mosher derivatives (HS Mosher et. Al. J. org. Chem. 34, 2543 (1969)).

N-protected amino acid aldehydes are produced according to B. Castro et. al. (Synthesis 1983, 676).

The Wittig reaction of an N-protected amino acid aldehyde (preferably N-tert-butoxycarbonyl and benzyloxycarbonyl Protecting groups) takes place in a suitable versus Bases inert solvents, such as ether, THF, toluene, DMF, DMSO or dimethoxyethane. As phosphonium salts preferably alkyl, arylalkyl and heteroarylalkyl triphenylphosphonium Chlorides, bromides and iodides are used. As bases for the deprotonation of the phosphonium salts can Alkali metal alcoholates, such as potassium O-tert-butoxide, sodium methylate, Alkali metal hydrides, such as sodium or potassium hydride, organometallic bases, such as n-butyllithium, s-butyllithium, methyllithium or phenyllithium, sodium amide as well as alkali metal salts of organic nitrogen bases, such as lithium diisopropylamide can be used.

The general in the compounds of the invention Formula I contained substituted 4-amino-3-hydroxybutyric acids  are known from the literature and are Rich et. al. J. Org. Chem. 43, 3624 (1978). The necessary for the preparation of compounds of formula I. Before and after operations such as introduction and spin-off of protecting groups are known from the literature and are e.g. B. in W. W. Greene, "Protective Groups in Organic Synthesis" described. Salts of compounds of formula I. with salt-forming groups in a manner known per se made by z. B. a compound of formula I. with a basic group with a stoichiometric Amount of a suitable acid. Mixtures of stereoisomers, especially mixtures of diastereomers that are used racemic amino acids A or B can occur in in a known manner, for example by fractional Crystallization or separated by chromatography will. The compounds of formula I according to the invention have enzyme-inhibiting properties; especially inhibit the effects of the natural enzyme renin. Renin is a proteolytic enzyme from the class of Aspartyl proteases which result from various stimuli (Volume depletion, sodium deficiency, β-receptor stimulation) from the juxtagiomerular cells of the kidney into the bloodstream is secreted. There it splits from the Liver excreted angiotensinogen the decapeptide angiotensin 1 from. This is achieved through "aniotensin converting enzyme "(ACE) converted to angiotensin 2. Angiotension 2 plays an essential role in blood regulation because it directly increases blood pressure through vascular contraction. In addition, it stimulates the secretion of aldosterone the adrenal gland and in this way increases over the inhibition the sodium excretion the extracellular fluid volume, which in turn contributes to an increase in blood pressure. Inhibitors of the enzymatic activity of renin a reduced formation of angiotensin 1, which is a reduced angiotensin 2 formation. The  Decrease in the concentration of this active peptide hormone is the direct cause of hypotensive Effect of renin inhibitors.

The effectiveness of renin inhibitors can be checked by in vitro tests. The reduction in the formation of angiotensin 1 in various systems (human plasma, pig renin) is measured. For this, z. B. human plasma, which contains both renin and angiotensinogen, incubated at 37 ° C with the compound to be tested. The concentration of angiotensin 1 formed during the incubation is then measured using a radioimmunoassay. The compounds of general formula I described in the present invention show in the in vitro tests used inhibitory effects at concentrations of about 10 ^-5 to 10 ^-10 mol / l.

Renin inhibitors lower blood pressure in salt-depleted animals. Because human renin differs from the renin other species are distinguished from in vivo tests Renin inhibitors primates (marmosets, rhesus monkeys) are used. Primate renin and human renin are in theirs Sequence largely homologous. By i. v. Injection of furosemide endogenous renin release is stimulated. Subsequently are the test connections by continuous Infusion administered and its effect on blood pressure and heart rate is measured. The compounds of the present Invention are in a dose range of about 0.1-5 mg / kg i. v. effective. The one in the present Compounds of the general formula described in the invention I can use it as an antihypertensive drug, as well as for treatment heart failure.

The invention therefore also relates to the use of compounds of formula I as a medicinal and pharmaceutical Preparations containing these compounds. Is preferred use in humans.  

Pharmaceutical preparations contain an effective amount of the active ingredient of formula I together with an inorganic or organic pharmaceutically usable carrier contain. The application can be intranasal, intravenous, Subcutaneously or orally. The dosage of the active ingredient depends on the warm-blooded species, body weight, Age and depending on the type of application.

The pharmaceutical preparations of the present invention are known in solution, mixing, granulating or coating process.

For an oral use form, the active compounds with the usual additives such as carriers, Stabilizers or inert diluents mixed and by usual methods in suitable dosage forms brought, such as tablets, coated tablets, capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. As an inert carrier can e.g. B. gum arabic, magnesium carbonate, potassium phosphate, Milk sugar, glucose, magnesium stearyl fumarate or starch, especially corn starch. Here can be prepared as dry or wet granules respectively. As an oily carrier or solvent come, for example, vegetable or animal oils such as sunflower oil and cod liver oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically tolerable Salts, if desired with the usual substances such as solubilizers, emulsifiers or other auxiliaries brought in solution, suspensions or emulsions. As Solvents come e.g. B. in question: water, physiological Saline solutions or alcohols, e.g. B. ethanol, propanediol or glycerin, as well as sugar solutions such as glucose or mannitol solutions, or a mixture of the different mentioned solvents.  

List of abbreviations used:

AA, 6 amino acid analysis Ac, 6 acetyl ACHPA, 6 [3S, 4S] -4-amino-3-hydroxy-5-cyclohexylpentanoic acid AHPPA, 6 [3S, 4S] -4-amino-3-hydroxy-5-phenylpentanoic acid BOC, 6-tert-butoxycarbonyl TLC, 6 thin layer chromatography DCC, 6 dicyclohexylcarbodiimide DNP, 62,4-dinitrophenyl DMF, 6 dimethylformamide DMSO, 6 dimethyl sulfoxide EE, 6 ethyl acetate FAB, 6Fast atom bombarded Fmoc, 69-fluorenylmethyloxycarbonyl HOBt, 61-hydroxybenzotriazole NEM, 6N-ethylmorpholine M, 6 molecular peak MeOH, 6 methanol MS, 6 mass spectrum R. T., 6Room temperature Mp, 6 melting point Sta, 6 [3S, 4S] -4-amino-3-hydroxy-6-methyl-heptanoic acid Tic, 6D, L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid THF, 6 tetrahydrofuran Z, 6 benzyloxycarbonyl

The other abbreviations used for amino acids correspond the three-letter customary in peptide chemistry Code like z. B. in Europ. J. Biochem. 138, 9-37 (1984) is described. Unless expressly stated otherwise they are always amino acids of the L configuration.

The following examples serve to explain the present Invention without being limited to this.

Example 1: (2S) -2-benzyloxy-3-phenyl-propanoyl-His-Sta-Ile-2- pyridylmethylamide

160 mg (2S) -2-benzyloxy-3-phenyl-propanoyl-His (DNP) -Sta-Ile-2-pyridylmethylamide are stirred in 7 ml DMF with 0.6 ml thiophenol at RT for 2 h. The mixture is concentrated in vacuo and digested 3 times with diisopropyl ether. After chromatography on silica gel (mobile phase EA / methanol 6: 1) and concentration of the product-containing fractions, (2S) -2-benzyloxy-3-phenylpropanoyl-His-Sta-Ile-2-pyridylmethylamide is obtained as a colorless powder.
R _f (EA / methanol 6: 1) = 0.4-0.5. MS (FAB): 754 (M + 1).

The starting material (2S) -2-benzyloxy-3-phenyl-propanoyl- His (DNP) -Sta-Ile-2-pyridylmethylamide is used in the following Working procedure produced:

a) 85 mg (2S) -benzyloxy-3-phenyl-propanoic acid, 226 mg H-His (DNP) -Sta-Ile-2-pyridylmethylamide and 83 mg HOBT are dissolved in 15 ml THF. Be at 0 to -5 ° C 91 mg of DCC, dissolved in 10 ml of THF, were added dropwise. The approach is overnight at R. T. Filter, concentrate in vacuo one, takes up with EE, extracted 2 times with 2N aq. Potassium carbonate solution, 1 time with water, dries over Magnesium sulfate and concentrates. After chromatography on Silica gel is obtained (2S) -2-benzyloxy-3-phenyl-propanoyl- His (DNP) -Sta-Ile-2-pyridylmethylamide as a slightly yellowish Powder. MS (FAB): 920 (M + 1).

b) Preparation of H-His (DNP) -Sta-Ile-2-pyridylmethylamide:

340 mg of Boc-His- (DNP) -Sta-Ile-2-pyridylmethylamide are dissolved in 10 ml of dioxane. While cooling with ice, 10 ml of dioxane saturated with HCl are added dropwise. After 2 h at RT, the mixture is concentrated in vacuo, dissolved in water, extracted once with CH ₂ Cl ₂ , with sat. aq. Na ₂ CO ₃ solution adjusted to pH 9 and extracted 3 times with CH ₂ Cl ₂ . After drying over MgSO ₄ and concentration in vacuo, H-His (DNP) -Sta-Ile-2-pyridylmethylamide is obtained as a yellow foam which can be used in the next coupling steps without further purification. MS (FAB): 682 (M + 1).

c) Preparation of BOC-His (DNP) Ile-2-pyridylmethylamide:

To 6.1 g BOC-His (DNP) -OH, 5.5 g H-Sta-Ile-2-pyridylmethylamide and 3.3 g HOBT in 100 ml THF at 0-5 ° C 3.7 g DCC, dissolved in 70 ml THF, added dropwise. After 4 h at RT, the mixture is filtered, concentrated and dissolved in EA. It is extracted 2 times with 2 N aq. K ₂ CO ₃ solution, once with water, dries over MgSO ₄ and concentrated in vacuo. After chromatography on silica gel (mobile phase EE), 8 g (70% yield) of Boc-His (DNP) -Sta-Ile-2-pyridylmethylamide are obtained. R _f (EA / methanol 10: 1) = 0.37 MS (FAB): 782 (M + 1).

d) Preparation of H-Sta-Ile-2-pyridylmethylamide:

Analogously to b) starting from 1 g of BOC-Sta-Ile-2-pyridylmethylamide H-Sta-Ile-2-pyridylmethylamide becomes colorless Get solid. Mp: 132 ° C.

e) Production of BOC-StaIle-2-pyridylmethylamide:

From 7.7 g of BOC-Sta-OH [manufactured according to J. Org. Chem. 43, 3624 (1978)], 6.2 g of H-Ile-2-pyridylmethylamide, 6.2 g HOBT and 6.9 g DCC are analogous to regulation (c) Obtained 12.1 g of BOC-Sta-Ile-2-pyridylmethylamide. Mp: 173 ° C.

f) Preparation of H-IIe-2-pyridylmethylamide

H-IIe-2-pyridylmethylamide is obtained from 6.6 g of BOC-IIe-2-pyridylmethylamide analogously to regulation (b). R _f (EA / methanol 1: 1) = 0.3-0.4.

g) Preparation of BOC-Ile-2-pyridylmethylamide

From 20 g of BOC-Ile-OH, 9.35 g of 2-picolylamine, 16.5 g of HOBT from 19.9 g of DCC, 18.5 g (67%) of Boc-Ile-2-pyridylmethylamide are obtained analogously to instruction (c) . MS: 321 (M).
The compounds of Examples 2-19 are prepared analogously to Example 1, starting from H-His- (DNP) -Sta-Ile-2-pyridylmethylamide and the corresponding N-terminal amino acid or carboxylic acid derivatives.

Example No. Connection

22-Benzyl-6,6-dimethyl-4-oxo-heptanoyl-His-Sta-Ile-2-pyridylmethylamide 3BOC- (Me) Phe-His-Sta-Ile-2-pyridylmethylamide 4BOC-D, L-β-2 -Thienylalanine-His-Sta-Ile-2-pyridylmethylamide 5N-3-phenylpropyl-Phe-His-Sta-Ile-2-pyridylmethylamide 6N-2,3-dichloro-4- (4-chloro-3-methylsulfonylbenzoyl) phenoxyacetyl -His-Sta-Ile-2-pyridylmethylamide 7N-4- (2,4-dichlorophenoxy) -butanoyl-His-Sta-Ile-2-pyridylmethylamide 8BOC-Tyr (Me) -His-Sta-Ile-2- pyridylmethylamide 9BOC-Tic-His-Sta-Ile-2-pyridylmethylamide 10BOC-Phg-His-Sta-Ile-2-pyridylmethylamide 11BOC-Tyr (Bzl) -His-Sta-Ile-2-pyridylmethylamide 12BOC-Tyr (t-But ) -His-Sta-Ile-2-pyridylmethylamide 13BOC-Phe (4-NO ₂ ) -His-Sta-Ile-2-pyridylmethylamide 14BOC-D-Trp-His-Sta-Ile-2-pyridylmethylamide 15Benzyloxycarbonyl- (E) -Dehydrophenylalkenyl- His-Sta-Ile-2-pyridylmethylamide 16Benzyloxycarbonyl- (Z) -Dehydrophenylalanyl- His-Sta-Ile-2-pyridylmethylamide 17D, L-2-tert.-Butoxycarbonylamino-4- (2-thienyl) - butanoyl- His-Sta-Ile-2-pyridylmethylamide 18BOC-D, L-β-3-thienylalanyl- His-Sta-Ile-2-pyridylmethylamide 19Fmoc-Phe-His-Sta-Ile-2-pyridylmethylamide

In order to confirm the structures of the peptides produced, different analytical and spectroscopic methods applied. The results are summarized in Table 1.

Table 1:

a) measured at 270 MHz; + means: in line with the specified structure

Example 20 BOC-Phe-β-2-thienylalanyl-Sta-Ile-2-pyridylmethylamide

0.7 g BOC-Phe-β-2-thienylalanine, 0.68 g H-Sta-Ile-2- pyridylmethylamide (Example 1d), 160 mg HOBT and 176 mg DDC are implemented together in the same way as in Example 1c. After chromatography on silica gel (eluent toluene / EA 1: 1) the title compound is obtained as a colorless solid. Mp 205 ° C. The one that serves as the starting link BOC-Phe-β-2-thienylalanine-OH is made according to the active ester method made from BOC-Phe-ONSucc and L-β-2-thienylalanine (J. Amer. Chem. Soc. 96, 1839).

Examples 21-23

The following are prepared as in Example 20:

Example No.

21BOC-Phe-Tyr (Me) -Sta-Ile-2-pyridylmethylamide 22BOC-Phe (4-Cl) -Sta-Ile-2-pyridylmethylamide 23BOC-Phe-D, L-3-thienylalanine-Sta-Ile-2-pyridylmethylamide

The analytical data of the compounds of the examples 20-23 are summarized in Table 2.

Example 24 N-acetyl- (2S, 3S, 6S) -octahydrocyclopenta [b] pyrrole-2-carbonyl- Phe-β-thienylalanyl-Sta-Ile-2-pyridylmethylamide

From H ₂ N-Phe-β-thienylalanyl-Sta-Ile-2-pyridylmethylamide (preparation from Example 20 analogous to working instructions 1b) and N-acetyl- (2S, 3aS, 6aS) -octahydrocyclopenta [b] pyrrole-2-carboxylic acid ( prepared according to EP-A-84 164) the title compound DCC / HOBT coupling is obtained as a colorless solid analogous to instruction 1a. MS (FAB): 838 (M + 1).

Example 25-32

The compounds of the examples are analogous to Example 24 25-32 manufactured.

Example No.

256-aminohexanoyl-Phe-β-2-thienylalanyl-Sta-Ile-2-pyridylmethylamide 26 dimethylaminoacetyl-Phe-β-2-thienylalanyl-Sta-Ile- 2-pyridylmethylamide 27Fmoc-Phe-β-2-thienylalanyl-Sta-Ile- 2-pyridylmethylamide 28Z-Phe-β-thienylalanyl-Sta-Ile-2-pyridylmethylamide 29cyclopentanoyl-Phe-β-2-thienylalanyl-Sta-Ile-2-pyridylmethylamide 30 (2S) -trans-4-hydroxy-1-acetylpyrrolidinyl- 2-carbonyl-Phe-β-2-thienylalanyl-Sta-Ile-2-pyridylmethylamide
312- (o, o-dichloroanilino) phenylacetyl-Phe-β-2-thienylalanyl-Sta-Ile-pyridylmethylamide 32N-acetyl- (2R, 3aR, 6aR) -octahydrocyclopentane [b] pyrrole-2-carbonyl-Phe-β -2-thienylalanyl-Sta-Ile-2-pyridylmethylamide

The analytical data of the compounds of the examples 25-32 are summarized in Table 2.

Table 2:

a) measured at 270 MHz; + means: in line with the specified structure

Example 33 BOC-Phe-His-Sta - [(3S, 4S) -4-methyl-1-phenyl- (E) -1-hexen-3- yl] amide

From 300 mg of BOC-Phe-His (DNP) -Sta - [(3S, 4S) -4-methyl-1-phenyl- (E) -1-hexen-3-yl] -amide is obtained analogously by DNP elimination Instructions 1 the title compound after chromatography on silica gel (mobile phase EA / MeOH = 20: 1) as a colorless solid. M (FAB): 731 (M + 1). R _f = 0.2-0.3 (EE / MeOH = 20: 1).

BOC-Phe-His (DNP) -Sta - [(3S, 4S) -4-methyl-1-phenyl- (E) -1- hexen-3-yl] amide is made by DCC / HOBT coupling BOC-PHE-His (DNP) -OH and the complementary statinamide prepared, its synthesis by BOC elimination analog Regulation 1b from BOC-Sta - [(3S, 4S) -4-methyl-1-phenyl- (E) - 1-hexen-3-yl] amide takes place. The manufacture of the above Amides is described below:

a) To 0.55 g BOC-Sta-OH, 0.45 g (3S, 4S) -3-amino-4-methyl-1-phenyl- (E) -1-hexene and 3.7 ml triethylamine in 20 ml of THF 1.3 ml of a 50 percent solution of propanephosphonic anhydride in methylene chloride are added dropwise with ice cooling. The mixture is left to stand at RT overnight, concentrated in vacuo and taken up in EA. The organic phase is 3 times with sat. aq. Na ₂ CO ₃ solution and extracted once with water. It is dried over MgSO ₄ , concentrated in vacuo and chromatographed on silica gel (mobile phase methylene chloride / EA = 8: 1). BOC-Sta - [(3S, 4S) -4-methyl-1-phenyl- (E) -1-hexen-3-yl] -amide is obtained as a colorless foam by concentrating the product-containing fractions. MS (FAB): 447 (M + 1). R _f = 0.16 (methylene chloride / EA = 8: 1).

b) Preparation of (3S, 4S) -3-amino-4-methyl-1-phenyl- (E) - 1-hexes:

From 0.5 g (3S, 4S) -3-N-tert-butoxycarbonylamino-4-methyl-1-phenyl- (E) -1-hexene by splitting off the BOC protective group in accordance with regulation 1b.

c) Preparation of (3S, 4S) -3-N-tert-butoxycarbonylamino 4-methyl-1-phenyl- (E) -1-hexene

5.8 g of benzyl triphenylphosphonium bromide and 1.37 g of potassium tert-butoxide are abs. THF stirred under argon at RT. At RT, a solution of 2.18 g of BOC isoleucinal (prepared according to Synthesis 1983, 676) in 17 ml of abs. THF added dropwise. After 30 min. at RT with 5% aq. Acidified NaHSO ₄ solution and extracted 3 times with methylene chloride. The organic phase is washed once with 0.1N HCl and twice with sat. NaHCO ₃ solution extracted, dried over MgSO ₄ and concentrated in vacuo. After chromatography on silica gel, the title compound is obtained as a colorless solid.

Example 34 BOC-Phe-His-Sta - [(3S, 4S) -4-methyl-1-phenyl-hexan-3-yl] amide

The title compound is obtained from 80 mg of Example 33 by hydrogenation at atmospheric pressure in methanol with Pd / C as a colorless solid MS (FAB): 733 (M + 1). R _f = 0.43 (EE / MeOH = 5: 1).

Example 35 BOC-Phe-His-Sta - [(3S) -1-phenyl- (E) -1-buten-3-yl] amide

Starting from BOC-alaninal, the title compound is obtained analogously to the reaction sequence described in Example 33. MS (FAB): 689 (M + 1). R _f = 0.2 (EE / MeOH = 10: 1).

Examples 36-50

The following compounds are analogous to Examples 33-35 produced:

Example No.

36BOC-Phe-His-Sta-3-phenyl-propylamide 37BOC-Phe-His-Sta - [(3S, 4S) -3-methyl-8-phenyl-octane 4-yl] amide 38BOC-Phe-His-Sta - [(3S, 4S) -3-methyl-7-phenyl-heptane 4-yl] amide 39BOC-Phe-His-Sta- (1S) -1-methyl-3-phenyl-propylamide 40BOC-Phe-His-Sta- (1S) -1-methyl-3- (4-methoxy-phenyl) - propylamide 41BOC-Phe-His-ACHPA- (1S) -1-methyl-3-phenyl-propylamide 42BOC-Phe-His-ACHPA- (1S) -1-methyl-3-phenyl-propylamide 43BOC-Phe-β-2-thienylalanyl-ACHPA- (1S) -1-methyl-3- phenylpropylamide 442-benzyl-3-phenylpropanoyl-His-ACHPA- (1S) -1-methyl- 3-phenyl-propylamide 45BOC-Phe-His-Sta - [(3S, 4S) -3-methyl-8-phenyl- (Z) - 5-octen-4-yl] amide 46BOC-Phe-β-2-thienylalanine-ACHPA- (1S) -1-methyl-3- (2-pyridyl) propylamide 47BOC-Phe-β-2-thienylalanyl-ACHPA - [(3S, 4S) -3-methyl- 6-phenyl-4-hexyl] amide 48Z-Phe-His-ACHPA- (1S) -1-methyl-3- (2-pyridyl) propylamide 49BOC-Phe-His-Sta- (1R, S) -1-methyl-2-phenoxy-ethylamide  50BOC-Phe-His-Sta-N-methyl - [(2S) -2-methyl-1- (4- methoxyphenyl) ethan-2-yl] amide

The analytical data of the compounds of the examples 33-50 are summarized in Table 3.

Table 3:

a) measured at 270 MHz; + means: in line with the specified structure

Example 51 BOC-Phe-β-2-thienylalanyl-ACHPA - [(3S) -3-methyl-1- (3- ethoxycarbonylmethoxy) phenyl-propan-3-yl] amide:

BOC-Phe-β-2-thienylalanine and H-ACHPA - [(3S) -3-methyl-1- (3-ethoxycarbonylmethoxy) phenyl-propan-3-yl] amide are obtained by DCC / HOBT coupling analogously to Example 1a, the title compound as a colorless solid. MS (FAB: 849 (M + 1). R _f = 0.1 (toluene / EE = 1: 1) H-ACHPA - [(3S) -3-methyl-1- (3-ethoxycarbonyl-methoxy) -phenyl -propan-3-yl] -amide is produced by BOC elimination of the corresponding precursor, which in turn is made from BOC-ACHPA-OH and (2S) -2-amino-4- (3-ethoxycarbonylmethoxy) by DCC / HOBT coupling - The preparation of the BOC-protected amine mentioned above is described below.

(2S) -2-tert-butoxycarbonylamino-4- (3-ethoxycarbonylmethoxy) - phenylbutene:

To 1.12 g of potassium tert-butoxide in 10 ml of abs. THF are dissolved under argon 5.5 g of 3- (methoxycarbonylmethoxy) benzyl triphenylphosphonium iodide in 30 ml of abs. THF added dropwise at RT. After 1/2 h at RT, 1.6 g of BOC-alaninal, dissolved in 15 ml of THF, are added dropwise. The mixture is stirred at RT for 1 h, mixed with 5% aq. NaHSO ₄ solution and extracted 3 times with CH ₂ Cl ₂ . The organic phase is washed once with 0.1 N aq. HCl and 2 times with sat. aq. NaHCO ₃ solution extracted, dried over MgSO ₄ and concentrated in vacuo. After chromatography on silica gel, the title compound is obtained as a colorless solid. MS: 335 (M +).

3- (methoxycarbonylmethoxy) benzyl triphenylphosphonium iodide:

10 g of 3-iodomethyl-phenoxyacetic acid methyl ester and 8.2 g of triphenylphosphine are boiled under reflux in 60 ml of toluene for 1 h. The product separates as oil. The solution is decanted off and the oily residue is chromatographed on silica gel (mobile phase: EA / MeOH = 10: 1). The title compound is obtained as a light yellow, amorphous solid. R _f = 0.31 (EE / MeOH = 10: 1).

3-Iodomethyl-phenoxyacetic acid methyl ester:

12 g of ethyl 3- (O-tosyl-hydroxymethyl) phenoxyacetate and 6 g of potassium iodide in 100 ml of acton until complete the reaction (D.C. control) under reflux cooked. It is filtered, concentrated in vacuo and chromatographed on silica gel (eluent: toluene / EA = 10: 1). The The title compound is obtained as a colorless oil.

3- (O-Tosyl-hydroxymethyl) phenoxyacetic acid ethyl ester:

To 2.4 g of sodium hydride in 100 ml of abs. DMF 21.2 g of 3-hydroxymethylphenoxyacetic acid methyl ester dissolved in 20 ml of DMF are added dropwise at 0.degree. After 1/2 h at 0 ° C., a solution of 19 g of p-toluenesulfonic acid chloride in 20 ml of THF is added dropwise, the mixture is stirred for 1/2 h at 0 ° C. and 10 h at RT. After concentration in vacuo and chromatography of the residue obtained on silica gel (Mobile phase: toluene / EA = 6: 1) the title compound is obtained. R _f = 0.5 (toluene / EA = 4: 1)

3-hydroxymethylphenoxyacetic acid methyl ester:

25 g of 3-hydroxybenzyl alcohol and 24 g of potassium tert-butoxide are dissolved in 200 ml of ethanol. 37 g of ethyl bromoacetate, dissolved in 100 ml of ethanol, are added dropwise at RT. After 12 h at RT, the mixture is concentrated in vacuo, taken up in ethyl acetate and the starting compound still present is removed by shaking twice with aq. 2n NaOH. The remaining organic phase is washed once with aq. 2N HCl, shaken once with water, dried over MgSO ₄ and concentrated in vacuo. 20 g of the title compound are obtained. R _f = 0.38 (toluene / EA = 2: 1).

Example 52 BOC-Phe-β-2-thienylalanyl-ACHPA - [(3S) -3-methyl-1- (3- carboxymethoxy) phenyl propan-3-yl] amide:

To 100 mg of Example 51, dissolved in 10 ml of dioxane, 3 ml of aq. 0.1N NaOH and stirred at RT until the methyl ester is completely saponified (TLC control). It is diluted with 50 ml of water and extracted twice with ethyl acetate. The aqueous phase is acidified with aq. 2N citric acid, extracted 3 times with CH ₂ Cl ₂ , drying over MgSO ₄ and concentrated in vacuo. The title compound is obtained as an amorphous solid. MS (FAB): 821 (M + 1). R _f = 0.3 (EE / MeOH = 10: 1).

Example 53 BOC-Phe-β-2-thienylalanyl-ACHPA - [(3S) -3-methyl-1- (3- (9- fluorenylmethyloxycarbonylamino-methyl)) - phenyl-propane 3-yl] amide:

The synthesis is carried out analogously to the reaction sequence given for Example 51 from BOC-Phe-β-2-thienylalanine and H-ACHPA - [(3S) -3-methyl-1- (3- (9-fluorenylmethyloxycarbonylamino-methyl)) - phenyl -propan-3-yl] amide. MS (FAB): 985 (M + 1). R _f = 0.3 (toluene / EA = 1: 1). The preparation of the C-terminal amine component is described below.

(2S) -2-tert-butoxycarbonylamino-4- [3- (9-fluorenylmethyloxycarbonylamino- methyl)] - phenylbutane:

0.5 g (2S) -2-tert-butoxycarbonylamino-4- (3-aminomethyl) phenylbutane are dissolved in 30 ml dioxane / H ₂ O = 1: 1 and 0.3 g NaHCO _{3 are} added at RT. 0.61 g of Fmoc-ONSucc is added and the mixture is stirred overnight at RT. The mixture is then filtered, the dioxane is spun off and the residue is washed with aq. Acidified in 1 HCl, extracted with CH ₂ Cl ₂ and dried over MgSO ₄ . After chromatography on silica gel, the product is obtained as a colorless solid. MS (FAB): 501 (M + 1). R _f = 0.4 (toluene / EA = 8: 1).

(2S) -2-tert-butoxycarbonylamino-4- (3-aminomethyl) phenyl- butane:

1 g (2S) -2-tert-butoxycarbonylamino-4- (3-cyano) - phenyl-butane is hydrogenated in 50 ml ethanol with Raney nickel at 2 bar. After filtration, the mixture is concentrated in vacuo, taken up in 10 ml of EA and extracted twice with aq. 2n citric acid. It is made alkaline with 2N NaOH and extracted 3 times with CH ₂ Cl ₂ . Drying with MgSO ₄ and concentration in vacuo gives the product as a yellow oil, which is used in the reaction step described above without further purification. MS: 278 (M +).

(2S) -2-tert-butoxycarbonylamino-4- (3-cyano) phenylbutane:

2.4 g of (2S) -2-tert-butoxycarbonylamino-4- (3-cyano) -phenyl- (E / Z) -3-butane are hydrogenated in 100 ml of methanol with Pd / C at RT under normal pressure. It is filtered, concentrated in vacuo, taken up in EA, extracted twice with aq. 2n citric acid solution, extracted 1 time with water, dried over MgSO ₄ and again concentrated in vacuo. 2.3 g of the title compound remain as residue. MS: 274 (M +). R _f = 0.63 (toluene / EA = 2: 1).

(2S) -2-tert-butoxycarbonylamino-4- (3-cyano-phenyl) - (E / Z) - 3-butene:

3.18 g of potassium tert-butoxide and 13.3 g of 3-cyanobenzyl triphenylphosphonium bromide are dissolved under argon in 160 ml of abs. THF stirred at RT for 1 h. Then a solution of 4.5 g Boc-Alaninal in 50 ml abs. THF added dropwise at RT. After 1 h at RT, the reaction mixture is mixed with 50 ml of a 2m NaHSO ₄ solution, the THF is distilled off in vacuo, diluted with water, extracted 3 times with CH ₂ Cl ₂ , dried over MgSO ₄ and concentrated in vacuo. After chromatography on silica gel (mobile phase: EA = 8: 1), 4 g of the title compound are obtained as an E / Z isomer mixture. MS: 272 (M +).

3-cyano-benzyl-triphenylphosphonium bromide:

10 g of 3-bromomethyl-acetonitrile and 15 g of triphenylphosphine are stirred in 150 ml of toluene for 1 h at R.T. Subsequently boil under reflux for 2 h, cool, filter the precipitated Phosphonium salt and dry it in vacuo. It 20 g of product are obtained. Mp: 315-317 ° C.

Example 54 BOC-Phe-β-2-thienylalanyl-ACHPA - [(3S) -3-methyl-1- (3-aminomethyl) - phenyl-propan-3-yl] amide:

60 mg of the compound from Example 53 are stirred in 10 ml of DMF with the addition of 2 ml of morpholine at RT. The mixture is concentrated in vacuo, digested with petroleum ether, decanted off the petroleum ether and concentrated again in vacuo. After chromatography on silica gel (mobile solvent: EE / MeOH solid. MS (FAB): 721 (m + 1). R _f = 0.3-0.4 (EE / MeOH = 4: 1).

The compound of Example 55 is prepared analogously to the scheme described above:
2-Phe-His-ACHPA - [(3S) -3-methyl-1- (3-aminomethyl) phenyl-propan-3-yl] amide. MS (FAB): 793 (M + 1). R _f = 0.3-0.4 (EE / MeOH = 5: 1)

Example 56 BOC-Phe-Tyr-AHPPA-Leu-2-pyridylmethylamide:

107.1 mg BOC-Phe-Tyr-OH are dissolved in 3 ml DMF and 50.7 mg HOBt and 51.6 mg DCC are added. After a reaction time of 1 h, 153.6 mg of H-AHPPA-Leu-2-pyridylmethylamide hydrochloride and 0.25 ml of NEM are introduced and the solution is stirred overnight. The precipitated urea is then filtered off, the filtrate is concentrated and the residue is taken up in ethyl acetate. The organic phase is washed with aq. Bicarbonate solution and saturated aq. Shaken out sodium chloride solution, dried over magnesium sulfate and concentrated. Column chromatographic purification on silica gel with methylene chloride (100/5) as the eluent gives the desired product as a colorless powder. R _f 0.65 in the eluent methylene chloride (90) / methanol (12) / water (0.8) acetic acid (0.8); MS (FAB): 823 (M + 1).

The synthesis of the starting compounds used for the above product and the examples below was carried out according to the following scheme.

a) H-AHPPA-Leu-2-pyridylmethylamide:

1.78 g of BOC-AHPPA-Leu-2-pyridylmethylamide are reacted analogously to Example 1b with dioxane / HCl to give H-AHPPA-Leu-2-pyridylmethylamide hydrochloride. R _f = 0.27 in the eluent methylene chloride (80) / methanol (20) / (acetic acid (1) / water (1).

b) BOC-AHPPA-Leu-2-pyridylmethylamide:

1.63 g of BOC-AHPPA-OH (prepared as described by D. Rich and ETO Sun in J. Med. Chem. 1980, 27-33) are mixed with 1.55 g of H-Leu-2-pyridylmethylamide hydrochloride as in Example 47 implemented. R _f 0.49 in the eluent methylene chloride (90) / methanol (10) / acetic acid (1).

c) H-Leu-2-pyridylmethylamide hydrochloride:

5.0 g of BOC-Leu-2-pyridylmethylamide are mixed with dioxane / HCl analogously to Example 1b. The product is obtained as a pale yellow, hygroscopic powder. R _f = 0.30 in the eluent methylene chloride (70) / methanol (30) / acetic acid (1) / water (1).

d) BOC-Leu-2-pyridylmethylamide:

8.0 g of BOC-Leu-OH are dissolved in 60 ml of DMF and 3.57 ml of picolylamine, 23.5 ml of NEM and 22.16 ml of propanephosphonic anhydride are added at -15 ° C. The mixture is left to stand at room temperature overnight, the solvent is removed in vacuo and the residue is taken up in ethyl acetate. The organic phase is washed with aq. Bicarbonate solution, KHSO ₄ / K ₂ SO ₄ solution and saturated aq. NaCl solution extracted, dried over magnesium sulfate and concentrated. The remaining oily crude product is dissolved in diisopropyl ether and crystallized by carefully adding n-hexane. Rhombic crystals of mp 82-83 ° C. are obtained. R _f = 0.41 in the eluent ethyl acetate (90) / methanol (10) MS (FAB) 321 (M + H).

e) Boc-Phe-Tyr-OH

1.32 g of BOC-Phe-OH is reacted analogously to Example 47 with 1.16 g of Boc-Phe-Tyr-OMe hydrochloride to BOC-Phe-OMe. The crude product obtained after working up is directly with a 50% solution of aq. Saponified in NaOH in dioxane to BOC-Phe-Tyr-OH. For working up, the mixture is diluted to 100 ml and extracted twice with ether. The aqueous phase is washed with aq. 2N HCl adjusted to pH 2.5 and extracted with ethyl acetate. After drying over MgSO ₄ and stripping off the solvent, the product is obtained as a colorless powder. R _f = 0.37 in the eluent methylene chloride (90) / methanol (12) / acetic acid (0.8) / water (0.8); MS (FAB) 429 (M + H).

f) N- (tert-butyloxycarbonyl) - [3S, 4S] -4-amino-5-cyclohexyl- 3-hydroxypentanoic acid (BOC-ACHPA-OH):

3.14 g of BOC-ACHPA-OEt are analogous to BOC-Sta-OEt with aq. NaOH saponified in dioxane. After working up, the semi-solid crude product is recrystallized from ethyl acetate / diisopropyl ether. Colorless fine acicular crystals of mp 108-110 ° C are obtained; Rotation value: [ α ] = -35.8 ° ( c = 1, methanol); R _f 0.6 in the eluent methylene chloride (90) / methanol (10) / acetic acid (1); MS (FAB) 316 (M + H).

N- (tert-butyloxycarbonyl) - [3S, 4S] -4-amino-5-cyclohexyl- 3-hydroxypentanoic acid ethyl ester (BOC-ACHFA-OEt):

The preparation was carried out analogously to the synthesis of BOC-Sta-OEt from BOC-cyclohexylalaninal and the lithium enolate of ethyl acetate. 89.1 ml of a 1.6 molar solution of n-butyllithium in hexane are added dropwise to a solution of 20 ml of diisopropylamine in 37 ml of tetrahydrofuran at -50 ° C. under protective gas (argon). After 20 minutes, the mixture is cooled to -78 ° C., 13.9 ml of ethyl acetate are added dropwise while maintaining the temperature, and the mixture is stirred for a further 15 minutes. A solution of 17.2 g of BOC-cyclohexylalaninal in 60 ml of tetrahydrofuran is then added dropwise at -75 ° C., the mixture is stirred for a further 5 minutes and then with 45 ml of aq. HCl added and adjusted to pH 2.5 at 0 ° C. After warming to room temperature, the mixture is extracted with ether and the organic phase is saturated with aq. Shaken out sodium chloride solution and concentrated after drying over MgSO ₄ . The crude product is separated into the diastereomers on silica gel (Grace®, 31 μm) using the solvent system ethyl acetate (1) / n-hexane (9). Elution first gives the desired 3S, 4S diastereomer as a colorless oil. R _f = 0.16 in hexane (8) / ethyl acetate (2); Rotation value [ α ]: -32.7 ° ( c = 1, methanol).

The later eluted 3R, 4S diastereomer is obtained as a crystalline substance with a melting point of 75-77 ° C. (ether / hexane) with the rotation value [ α ] = -20.8 ° ( c = 1, methanol); R _f = 0.12 in hexane (8) / ethyl acetate (2).

In analogy to the example above, the following were listed Connections by reaction of the corresponding  Dipeptides or acylated amino acids with H-AHPPA-Leu-2- pyridylmethylamide or H-ACHPA-Leu-2-pyridylmethylamide receive.

Example No. Connection

57BOC-Phe-Phe-AHPPA-Leu-2-pyridylmethylamide 58BOC-Phe-Cyclohexylglycyl-AHPPA-Leu-2-pyridylmethylamide 59BOC-Phe-D, L-3- (2-pyridyl) alanyl-AHPPA-Leu-2-pyridylmethylamide 60BOC-Phe-Trp-AHPPA-Leu-2-pyridylmethylamide 61BOC-Phe-Leu-AHPPA-Leu-2-pyridylmethylamide 62BOC-Phe-Cyclohexylalanyl-AHPPA-Leu-2-pyridylmethylamide 63BOC-Phe-Tyr (Me) -AHPPA- Leu-2-pyridylmethylamide 64BOC-Phe-His (τ-Me) -AHPPA-Leu-2-pyridylmethylamide 65BOC-Phe-Phg-AHPPA-Leu-2-pyridylmethylamide 66BOC-Phe-Asn-AHPPA-Leu-2-pyridylmethylamide 67BOC -Phe-D, L-3- (3-pyridyl) alanyl-AHPPA-Leu-2-pyridylmethylamide 68BOC-Phe-Met-AHPPA-Leu-2-pyridylmethylamide 69BOC-Phe-Met (O) -AHPPA-Leu-2 -pyridylmethylamide 70BOC-Phe-Met (O ₂ ) -AHPPA-Leu-2-pyridylmethylamide 71BOC-Phe-Asp-ACHPA-Leu-2-pyridylmethylamide 72BOC-Trp-His-AHPPA-Leu-2-pyridylmethylamide 73BOC-D, L -3- (2-Naphthyl) alanyl-Ile-AHPPA-Leu-2-pyridylmethylamide 74BOC-D, L-3- (1-naphthyl) alanyl-Ile-AHPPA-Leu-2-pyridylmethylamide 753-phenylpropionyl-Ile-AHPPA -Leu-2-pyridylmethylamide 76 dibenzylacetyl-Ile-AH PPA-Leu-2-pyridylmethylamide 77BOC-Phe-β-2-thienylalanyl-AHPPA-Leu-2-pyridylmethylamide

Table 4:

a) measured at 60 or 270 MHz; + means: in harmony with the specified structure.

Example 78 Z-Phe-β-thienylalanyl-Sta-Ile-8-tert-butoxycarbonylamino-octylamide:

The title compound is obtained from Z-Phe-β-2-thienylalanine and H-Sta-Ile-8-tert-butoxycarbonylamino-octylamide analogously to Example 56 by DCC / HOBT coupling as a colorless solid. MS (FAB): 951 (M + 1). R _f : 0.5 (EE)

Example 79 Z-Phe-β-2-thienylalanyl-Sta-Ile-8-amino-octylamide:

The title compound is obtained as a colorless powder from 100 mg of Example 78 by splitting off the Boc protective group analogously to Example 1b. MS (FAB): 851 (M + 1). R _f : 0.2 (EE / MeOH = 5: 1).

Example 80 BOC-Phe-His-Sta-Leu-2-N- (2-pyrimidinyl) aminoethylamide:

BOC-Phe-His (DNP) -OH and H-Sta-Leu-2-N- (2-pyrimidinyl) - aminoethylamide become Boc-Phe-His (DNP) -Sta-Leu-2-N- (2- pyrimidinyl) - aminoethylamide analogous to Example 56 obtained by DCC / HOBT coupling as a yellow solid. The DNP protective group is split off as described in Example 1. The title compound is obtained as a colorless solid after purification by column chromatography. MS (FAB): 793 (M + 1). R _f : 0.1 (CH ₂ Cl ₂ / MeOH / AcOH / H ₂ O = 100: 90: 10: 1). Mp: 126 ° C (dec.).

Example 81 N-acetyl- (2S-3aS, 6aS) octahydrocyclopenta [b] pyrrole-2- carbonyl-Phe-Leu-Sta- (4-amido-1-benzyl-piperidine):

From N-acetyl- (2S, 3aS, 6aS) -octahydrocyclopenta [b] pyrrole-2-carboxylic acid and H-Phe-Leu-Sta- (4-amido-1-benzyl-piperidine) the title compound is analogous to Example 25 by DCC / HOBT coupling obtained as a colorless solid. MS (FAB): 900 (M + 1). R _f = 0.4 (CH ₂ Cl ₂ / MeOH / AcOH / H ₂ O = 85: 1: 1: -1. [ Α ] = -49.9 ° ( c = 1, MeOH).

Example 82 BOC-Phe-His-Sta-Leu-Asn-NH ₂ :

BOC-Phe-His (DNP) -OH and H-Sta-Leu-Asn-NH ₂ becomes BOC-Phe-His- (DNP) -Sta-Leu-Asn-NH ₂ analogously to Example 56 by DCC / HOBT coupling obtained as a yellow solid. The DNP protective group is split off as described in Example 1. The title compound is isolated as a colorless solid after purification by column chromatography. MS (FAB): 786 (M + 1). R _f = 0.15 (CH ₂ Cl ₂ / MeOH / AcOH / H ₂ O = 80: 20: 1: 1) mp: 213-215 ° C.

The compounds of the examples are analogous to Example 82 83-86 from BOC-Phe-β-2-thienylalanine and the corresponding Amino component produced.

Example No. Connection

83BOC-Phe-β-2-thienylalanyl-Sta-Ile-Arg-OH 84BOC-Phe-β-2-thienylalanyl-Sta-Ile-Arg-OMe 85BOC-Phe-β-2-thienylalanyl-Sta-Ile arginol 86BOC -Phe-β-2-thienylalanyl-Sta-Ile-Arg-NH ₂

The analytical data of compounds 83-86 are given in Table 5 summarized.

Example 87 Z-Phe-β-2-thienylalanyl-Sta-Ile-3- (tert-butoxycarbonylaminomethyl) - benzylamide:

The title compound is obtained from Z-Phe-β-2-thienylalanine and H-Sta-Ile-3- (tert-butoxycarbonylamino-methyl) -benzylamide by DCC / HOBT coupling analogously to Example 20 after chromatographic purification as a colorless solid. MS (FAB): 941 (M + 1). R _f = 0.3 (EE).

Example 88 Z-Phe-β-2-thienylalanyl-Sta-Ile-3- (aminomethyl) benzylamide:

The title compound is prepared from 100 mg of the compound from Example 87 by elimination of BOC analogously to instruction 1b. MS (FAB): 841 (M + 1). R _f : 0.2 (EE / MeOH = 4: 1).

The compounds are analogous to Example 88 or Example 87 of Examples 89-91. Your analytical data are summarized in Table 5.

Example No. Connection

89Fmoc-Phe-β-2-thienylalanyl-Sta-Ile-3- (aminomethyl) - benzylamide 90Z-Phe-β-2-thienylalanyl-ACHPA-Ile-3- (aminomethyl) - benzylamide 912- (9-fluorenylmethyloxycarbonylamino) -4- (2-thienyl) - butanoyl-His-Sta-Ile-3- (aminomethyl) benzylamide

Example 92 Z-Phe-β-2-thienylalanyl-ACHPAIle-3- (guanidinomethyl) - benzylamide:

From 100 mg of the compound from Example 88 and 80 mg 1-guanidyl-3,5-dimethyl-pyrazole nitric acid salt receive the title compound according to the literature (Houben-Weyl, Methods of Organic Chemistry, Volume 15/1 P. 532). MS (FAB): 883 (M + 1).

Example 93 Z-Phe-β-2-thienylalanyl staI- (3-tert-butoxycarbonylmethoxy- ) benzylamide:

345 mg of Z-Sta-Ile-L-3- (tert-butoxycarbonylmethoxy) benzylamide are catalyzed by. Hydrogenation (MeOH, Pd / C) converted into H ₂ ^N- Sta-Ile-3- (tert-butoxycarbonylmethoxy) benzylamide. Without further purification, this is coupled with 315 mg of Z-Phe-β-2-thienylalanine ONSucc to give the title compound mentioned. MS (FAB): 942 (M + 1). R _f = 0.3 (EE).

Example 94 Z-Phe-β-2-thienylalanyl-Sta-Ile-3- (carboxy) benzylamide:

100 mg of the compound from Example 93 are stirred in 10 ml of CH ₂ Cl ₂ / CF ₃ CO ₂ H = 1: 1 at RT until the reaction is complete (TLC control). After concentration in vacuo, the title compound is isolated as a chromatographically uniform solid. MS (FAB): 886 (M + 1). R _f = 0.4 (EE / MeOH = 4: 1).

The compounds are analogous to Example 93 or Example 94 of Examples 95-96. Your analytical Data are summarized in Table 5.

Example No. Connection

95Z-Phe-β-2-thienylalanyl-ACHPA-Ile-3- (tert-butoxycarbonylmethoxy) - benzylamide 96Z-Phe-β-2-thienylalanyl-ACHPA-Ile-3- (carboxymethoxy-benzylamide  

Table 5

a) measured at 60 or 270 MHz; + means: in harmony with the specified structure

Claims (22)

1. Compound of formula I. in which

• R ⁴ a ₁ ) denotes a radical of the formula II or III,
  • wherein
    R ^{5 is} hydrogen or (C ₁ -C ₇ ) alkyl and
    R ^{6 is} hydrogen, (C ₁ -C ₇ ) -alkyl or by hydroxy, (C ₁ -C ₅ ) -alkoxy, (C ₁ -C ₅ ) -alkylthio, carboxy, (C ₁ -C ₅ ) -alkoxycarbonyl, Cl, Br, (C ₁ -C ₅ ) alkylamino, di- (C ₁ -C ₅ ) alkylamino, (C ₁ -C ₅ ) alkoxycarbonylamino or (C ₁ -C ₁₅ ) aralkyloxycarbonylamino monosubstituted (C ₁ - C ₇ ) alkyl,
  • m = 0, 1, 2, 3 or 4,
    n = 1, 2, 3, 4, 5 or 6,
    the double bond in the rest of the formula III in the case n = 0 preferably has the E configuration, otherwise preferably the Z configuration and
    Ar for (C ₆ -C ₁₄ ) aryl, which may be replaced by one or two identical or different radicals from the series F, Cl, Br, J, hydroxy, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkoxycarbonyl, amino, (C ₁ -C ₇ ) alkylamino, di (C ₁ -C ₇ ) alkylamino, carboxy, carboxymethyloxy, amino (C ₁ -C ₇ ) -alkyl, (C ₁ -C ₇ ) -alkylamino- (C ₁ -C ₇ ) -alkyl, di- (C ₁ -C ₇ ) -alkylamino- (C ₁ -C ₇ ) -alkyl, (C ₁ -C ₇ ) alkoxycarbonylmethoxy, carbamoyl, sulfamoyl, (C ₁ -C ₇ ) alkoxysulfonyl, sulfo and guanidinomethyl, or for the remainder of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaromatic with at least 1 C atom, 1-3 N atoms and / or 1 S or O atom as ring members, where Ar can also be bonded via -O-,
• a ₂ ) a residue of an amino acid from the series phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, β-2-thienylalanine, β-3-thienylalanine, 4-chlorophenylalanine, 4-chlorophenylalanine, methionine sulfone linked via a peptide bond Methionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine, O-methyltyrosine, O-benzyltyrosine, O-tert.-butyltyrosine, phenylglycine, 1-naphthylalanine, 2-naphthylalananoline 4-naphthylalanine , 3-fluorophenylalanine, 4-fluorophenylalanine, norleucine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, homophenylalanine, DOPA, O-dimethyldopa, 2-amino-4- (2-thienyl) butyric acid, 2-amino -4- (3-thienyl) butyric acid, 3- (2-thienyl) serine, (Z) -dehydrophenylalanine and (E) -dehydrophenylalanine, whose C-terminal carboxyl group is free, reduced to CH ₂ OH or
  as an amide which has a C-terminus of the formula -NR ⁷ R ⁸ , in which R ⁷ and R ^{8 are} identical or different and are for
  • Hydrogen,
    (C ₁ -C ₁₀ ) alkyl optionally substituted by amino, (C ₁ -C ₅ ) alkoxycarbonylamino, (C ₇ -C ₁₅ ) aralkylcarbonylamino, heteroarylamino, in which the remainder of the heteroaromatic is as defined above under (a ₁ ) is hydroxy, (C ₁ -C ₅ ) alkoxy, sulfo, carboxy or (C ₁ -C ₅ ) alkoxycarbonyl is monosubstituted,
    (C ₆ -C ₁₄ ) aryl (C ₁ -C ₄ ) alkyl, optionally in the aryl part by amino, carboxy, (C ₁ -C ₅ ) alkoxycarbonyl, amino (C ₁ -C ₅ ) alkyl , (C ₁ -C ₅ ) alkoxycarbonylamino- (C ₁ -C ₅ ) alkyl, (C ₇ -C ₁₅ ) aralkoxycarbonylamino- (C ₁ -C ₅ ) alkyl, (C ₁ -C ₅ ) alkoxycarbonyl - (C ₁ -C ₅ ) alkoxy, carboxy- (C ₁ -C ₅ ) alkoxy or guanido (C ₁ -C ₅ ) alkoxy is monosubstituted, or
    Heteroaryl- (C ₁ -C ₄ ) -alkyl, where the rest of the heteroaromatic is defined as Ar under (a ₁ ), or represents a radical of the formula IV,
    wherein
    R ^{5 is} hydrogen or (C ₁ -C ₇ ) alkyl and
    R ^{6 is} hydrogen, (C ₁ -C ₇ ) -alkyl or by hydroxy, (C ₁ -C ₅ ) -alkoxy, (C ₁ -C ₅ ) -alkylthio, carboxy, (C ₁ -C ₅ ) -alkoxycarbonyl, Cl, Br, (C ₁ -C ₅ ) alkylamino, di- (C ₁ -C ₅ ) alkylamino, (C ₁ -C ₅ ) alkoxycarbonylamino or (C ₁ -C ₁₅ ) aralkyloxycarbonylamino monosubstituted (C ₁ - C ₇ ) alkyl, wherein p = 1, 2, 3, or 4, q = 4 or 5 and Q is N or CH or p = 0, q = 4 or 5 and Q is CH and wherein a CH ₂ group is in the ring NH, O, S, CO, N-Bzl, NZ or N-BOC can be replaced, or
• a ₃ ) means a residue of a dipeptide from the series Leu-Asn, Ile-His, Ile-Arg and Ile-Lys linked via a peptide bond, its C-terminus as a free COOH group, which optionally reduces to the CH ₂ OH group is present as CONH ₂ or as COOR ⁹ with R ⁹ = (C ₁ -C ₇ ) alkyl and in which the ε-amino function of the lys is optionally by (C ₁ -C ₅ ) alkoxycarbonyl or (C ₇ -C ₁₅ ) -Aralkyloxycarbonyl is protected;
• R ¹ b ₁ ) is absent or is hydrogen,
• b ₂ ) (C ₁ -C ₂₀ ) alkyl, which may be replaced by one, two or three identical or different radicals from the series hydroxy, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkanoyloxy, Carboxy, (C ₁ -C ₇ ) alkoxycarbonyl, (C ₁ -C ₈ ) alkanoyloxy, Cl, Br, amino, (C ₁ -C ₇ ) alkylamino, di- (C ₁ -C ₇ ) alkylamino, (C ₁ -C ₅ ) alkoxycarbonylamino or (C ₇ -C ₁₁ ) aralkyloxycarbonylamino is substituted,
  (C ₃ -C ₈ ) cycloalkyl,
  (C ₃ -C ₈ ) cycloalkyl- (C ₁ -C ₁₀ ) alkyl or
  (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₈ ) alkyl, which in the aryl part is optionally substituted by one or two identical or different radicals from the series F, Cl, Br, hydroxy, (C ₁ -C ₇ ) -Alkoxy, (C ₁ -C ₇ ) -alkyl, (C ₁ -C ₇ ) -alkoxycarbonyl, amino or trifluoromethyl is substituted, or
• b ₃ ) is a radical of the formula V, Ra-W-, 6 (V)
  • wherein W is -CO-, -O-CO-, -SO ₂ - or -NH-CO- and Ra is hydrogen, (C ₁ -C ₁₀ ) alkyl, which is optionally mono- or di-unsaturated, and optionally by up to 3 identical or different radicals from the series hydroxy, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkanoyloxy, carboxy, (C ₁ -C ₇ ) alkoxycarbonyl, Cl, Br, amino, (C ₁ -C ₇ ) alkylamino, di- (C ₁ -C ₇ ) alkylamino, (C ₁ -C ₅ ) alkoxycarbonylamino, (C ₇ -C ₁₅ ) aralkoxycarbonylamino or 9-fluorenylmethyloxycarbonylamino is monosubstituted,
    (C ₃ -C ₈ ) cycloalkyl,
    (C ₃ -C ₈ ) cycloalkyl- (C ₁ -C ₆ ) alkyl,
    (C ₆ -C ₁₄ ) aryl which is optionally substituted by one or two identical or different radicals from the series F, Cl, Br, J, hydroxy, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) Alkyl, (C ₁ -C ₇ ) -alkoxycarbonyl, amino, optionally substituted with up to 2 halogen-substituted anilino and trifluoromethyl,
    (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₆ ) alkyl, wherein the aryl part is optionally as defined above for aryl, heteroaryl or heteroaryl- (C ₁ -C ₆ ) alkyl, the rest of the heteroaromatic in each case as Ar is defined under (a ₁ ), means, or
• b ₄ ) a radical from the series (2S) -trans-4-hydroxy-1-acyl-pyrrolidinyl-2-carbonyl, 5-pyrrolidone-2S-carbonyl, α-methoxycarbonyl-α-acylacetyl, 1-acyl- (2R , 3aR, 6aR) -octahydro-cyclopenta [b] pyrrole-2-carbonyl and 1-acyl- (2S, 3aS, 6aS) -octahydro-cyclopenta [b] pyrrole-2-carbonyl, with acyl meaning (C ₁ -C ₆ ) alkanoyl, (C ₁ -C ₅ ) alkoxycarbonyl or (C ₇ -C ₁₅ ) alkoxycarbonyl or (C ₇ -C ₁₅ ) aralkyloxycarbonyl,
• A c ₁ ) denotes a radical of the formulas VI or VII,
  • in which
    r = 1, 2 or 3,
    s = 1, 2 or 3 and
    R is (C ₁ -C ₇ ) alkyl, or
• c ₂ ) denotes a residue of an amino acid linked to R ¹ and C-terminal to B of an amino acid which is defined as under (a ₂ ),
• B d ₁ ) if R ^{4 is} as defined under (a ₁ ), is an N-terminal with A and C-terminal with the NH group of formula I linked residue of an amino acid which is as defined under (a ₂ ), or
• d ₂ ) if R ^{4 is} as defined under (a ₂ ) or (a ₃ ), an N-terminally linked A and C-terminally linked to the NH group of formula I of an amino acid from the 2-thienylalanine series, 3 -Thienylalanine, cyclohexylglycine, phenylglycine, aspartic acid, asparagine, glutamic acid, glutamine and methionine sulfone,
• R ^{2 is} hydrogen, (C ₁ -C ₁₀ ) alkyl, (C ₄ -C ₇ ) cycloalkyl, (C ₄ -C ₇ ) cycloalkyl (C ₁ -C ₄ ) alkyl, (C ₆ -C ₁₄ ) Aryl or (C ₆ -C ₁₄ ) aryl (C ₁ -C ₄ ) alkyl and
• R ^{3 is} hydrogen, (C ₁ -C ₁₀ ) alkyl, (C ₆ -C ₁₄ ) aryl or (C ₆ -C ₁₄ ) aryl (C ₁ -C ₄ ) alkyl,

and their physiologically tolerable salts.   2. A compound of formula I according to claim 1, in which A, B and / or R ⁴ each represent the residue of an L-amino acid or the residue of an L-amino acid derivative. 3. A compound of formula I according to claim 1 or 2, in which R ^{4 is} as defined in claim 1 under (a ₁ ). 4. A compound of formula I according to claim 1 or 2, in which R ^{4 is} as defined in claim 1 under (a ₂ ). 5. A compound of formula I according to claim 1 or 2, in which R ^{4 is} as defined in claim 1 under (a ₃ ). 6. A compound of formula I according to claim 3, in which R ^{5 is} hydrogen or methyl. 7. A compound of formula I according to claim 3 or 6, in which R ^{6 is} hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, (C ₁ -C ₅ alkoxycarbonylmethyl, (C ₁ -C ₅ ) -Alkoxycarbonylethyl or methylthioethyl mean. 8. A compound of formula I according to any one of claims 3, 6 or 7, in which Ar is phenoxy, phenyl, 2-, 3- or 4-pyridyl, 4-imidazolyl, 1-, 3- or 4-isoquinolyl, 2- , 3- or 4-carboxyphenyl, 2-, 3- or 4- (C ₁ -C ₇ ) alkoxycarbonylphenyl, preferably 3-methoxycarbonylphenyl or 3-tert-butoxycarbonylphenyl, 2-, 3- or 4-aminophenyl, mono- or di (C ₁ -C ₇ ) alkylaminophenyl, preferably 3-methylaminophenyl or 3-dimethylaminophenyl, 2-, 3- or 4-carbamoylphenyl, 3-sulfamoylphenyl, 3-sulfophenyl, amino- (C ₁ -C ₇ ) - alkylphenyl, preferably 2-, 3- or 4-aminomethylphenyl, 3- (methylaminomethyl) phenyl, 3- (N, N-dimethylaminomethyl) phenyl, (C ₁ -C ₇ ) alkoxycarbonylmethoxyphenyl, preferably 2-, 3- or 4-methoxycarbonylmethoxyphenyl or 3-tert-butoxycarbonylmethoxyphenyl, 2-, 3- or 4-carboxymethyloxyphenyl, (C ₁ -C ₇ ) alkoxyphenyl, preferably 2-, 3- or 4-methoxyphenyl, or 2-, 3- or 4 - Guanidinomethylphenyl stands. 9. A compound of formula I according to claim 4, in which R ^{4 represents} the residue of an amino acid amide with the C-terminus -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 are the} same or different and methyl, 10-aminodecyl, 9- Aminononyl, 8-aminooctyl, 7-aminoheptyl, 6-aminohexyl, 5-aminopentyl, 4-aminobutyl or the N-BOC or NZ-protected derivatives of the above ω-aminoalkyl radicals, (2-pyrimidinylamino) ethyl, 2- Sulfoethyl, 8-carboxyoctyl, 7-carboxyheptyl, 6-carboxyhexyl, 7-methoxycarbonylheptyl, 2-pyridylaminoethyl, phenethyl or benzyl, both of which are optionally in the phenyl part in the 2-, 3- or 4-position by amino, in 2-, 3- or 4-position by aminomethyl, in 3-position by BOC-aminomethyl or guanidinomethyl, in 2-, 3- or 4-position by carboxy, in 3-position by tert-butoxycarbonyl, in 2-, 3- or 4- Position are substituted by carboxymethoxy or in the 3-position by tert-butoxycarbonylmethoxy, 2-, 3- or 4-pyridylmethyl, 4-imidazolylethyl, 3-indolylethyl, 4-piperidyl, 4-piperidy 1- (C ₁ -C ₄ ) alkyl, 2-oxo-1-pyrrolidinyl), 2-oxo-1-pyrrolidinyl) - (C ₁ -C ₄ ) alkyl,
is preferably 4- (N-benzyl) piperidyl, 3-morpholinopropyl or 3- (2-oxo-1-pyrrolidinyl) propyl or -NR ⁷ R ^{8 is} morpholino. 10. The compound of formula I according to claim 5 in which R ⁴ represents Leu-Asn-NH _2, Ile-His-OH, Ile-His-NH _2, Ile-Arg-NH _2, Ile-Arg-OH, Ile Arg-OCH ₃ , Ile-Arginol, Ile-Lys- (BOC) -OCH ₃ , Ile-Lys-OCH ₃ , Ile-Lys-OH or Ile-Lys-NH ₂ . 11. A compound of formula I according to any one of claims 1-10, in which R ^{1 is} absent, is hydrogen or for (C ₁ -C ₁₀ ) alkyl, cyclopentyl, cyclohexyl, cyclopentyl- (C ₁ -C ₁₀ ) alkyl , Cyclohexyl- (C ₁ -C ₁₀ ) -alkyl, optionally substituted phenyl- (C ₁ -C ₈ ) -alkyl, H ₂ N- (C ₁ -C ₁₀ ) -alkyl, HO- (C ₁ -C ₁₀ ) -Alkyl, (C ₁ -C ₄ ) -alkoxy- (C ₁ -C ₁₀ ) -alkyl, (C ₁ -C ₄ ) -alkoxycarbonyl- (C ₁ -C ₁₀ ) -alkyl, carboxy- (C ₁ -C ₁₀ ) -alkyl or (C ₁ -C ₈ ) -alkanoyloxy- (C ₁ -C ₁₀ ) -alkyl. 12. A compound of formula I according to any one of claims 1-10, in which R ¹ (C ₁ -C ₁₁ ) alkanoyl, preferably n-decanoyl, formyl, acetyl, pivaloyl, isovaleryl or isobutyryl, optionally protected amino- (C ₁ -C ₁₁ ) - alkanoyl, preferably 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 4-N-tert.-butoxycarbonylaminobutyryl, 5-N-tert.butoxycarbonylaminopentanoyl or 6-N-tert.-butoxycarbonylaminohexanoyl, di- (C ₁ -C ₇ ) alkylamino (C ₁ -C ₁₁ ) alkanoyl, preferably dimethylaminoacetyl, (C ₄ -C ₉ ) cycloalkanoyl, preferably cyclopropanoyl, cyclobutanoyl, cyclopentanoyl or cyclohexanoyl, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₁₁ ) alkanoyl, preferably phenylacetyl, phenylpropanoyl or phenylbutanoyl, 2- (o, o-dichloroanilino) phenylacetyl, 2- (N-benzyl- o, o-dichloroanilino) phenylacetyl, optionally by halogen, ( C ₁ -C ₇ alkyl, (C ₁ -C ₇ ) alkoxy, (C ₁ -C ₇ ) alkoxycarbonyl substituted benzoyl, preferably 4-chlorobenzoyl, 4-methylbenzoyl, 2-methoxycarbonylbenzoyl or 4-Met hoxybenzoyl, pyrrolyl-2-carbonyl, pyridyl-3-carbonyl, benzylsulfonyl, (C ₁ -C ₁₀ ) alkoxycarbonyl, preferably methoxycarbonyl or tert-butoxy-carbonyl, preferably substituted by halogen-substituted (C ₁ -C ₁₀ ) alkoxycarbonyl 2,2,2-trichloroethoxycarbonyl or 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, (C ₆ -C ₁₄ ) aryl- (C ₁ -C ₆ ) alkoxycarbonyl, preferably benzyloxycarbonyl or 9-fluorenylmethylcarbonyl, ( 2S) -trans-4-hydroxy-1-acetylpyrrolidinyl-2-carbonyl, α-methoxycarbonyl-α-benzyloxycarbonylaminoacetyl, N-acetyl- (2S, 3aS, 6aS) -octahydrocyclopenta [b] pyrrole-2-carbonyl or N-acetyl - (2R, 3aR, 6aR) -octahydrocyclopenta [b] pyrrole-2-carbonyl. 13. A compound of formula I according to any one of claims 1, 2, 4, 9, 11 or 12, in which R ^{4 is} a residue of an amino acid from the series phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid , β-2-thienylalanine, β-3-thienylalanine, 4-chlorophenylalanine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine, O-methyltyrosine, O-benzyltyrosine, O-benzyltyrosine Butyltyrosine, phenylglycine, 1-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, norleucine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, homophenylalanine, 2-amino-4- (2-thienyl) butyric acid, (Z ) -Dehydrophenylalanine or (E) -dehydrophenylalanine means whose C-terminus is present as defined in claim 1. 14. A compound of formula I according to any one of claims 1- 3, 6-8, 1 or 12 in which B is an N-terminal with A and C-terminal with the NH group of formula I. linked residue of an amino acid which means like the amino acids is defined in claim 13. 15. A compound of the formula I as claimed in any of claims 1-14, in which A is a radical which is N-terminally linked to R ¹ and C-terminally linked to B and is another amino acid which is defined as the amino acids in claim 13 (2S) - O-benzyl-3-phenyl-propanoyl or (2R, S) -2-benzyl-4-oxo-6,6-dimethyl-6-heptanoyl. 16. A compound of formula I according to any one of claims 1-15, in which R ^{2 is} cyclohexylmethyl, benzyl or isobutyl. 17. A compound of formula I according to any one of claims 1-16, in which R ^{3 is} hydrogen, ethyl, sec-butyl, isobutyl, benzyl, phenethyl, or 3-phenylpropyl. 18. Process for the preparation of a compound of formula I. according to one of claims 1-17, characterized in that a fragment with a terminal carboxyl group or reactive derivative with a corresponding one Coupled fragment with free amino group, if necessary to protect further functional groups (one) temporarily introduced protective group (s) and the so compound obtained, if appropriate, physiologically in it tolerated salt transferred. 19. Use of a connection according to one of the claims 1-17 as a remedy. 20. Use of a connection according to one of the claims 1-17 as a remedy in the treatment of high blood pressure. 21. Pharmaceutical composition containing a compound according to any of claims 1-17.